Based on Preliminary Data, we hypothesized that loss of retinoic acid receptor function might promote dysregulated growth and loss of epithelial polarity. We now report that retinoids and the retinoic acid receptor-beta are important regulators of proliferation and polarity normal mammary epithelial cells through modulation of 1) the CREB-binding protein, CBP and 2) laminin 5 expression. As proposed in Objective lA, and described in the BODY of this report, we have been successful in identifying a retinoid-regulated gene, the CREB-binding protein, CBP whose function is important in mammary epithelial cell growth regulation and polarity. CBP is a known critical regulator of retinoid-signaling, however, the role of CBP in regulating growth and epithelial cell polarity has been previously unknown. As proposed in Objective 1B, we have suppressed CBP function in mammary epithelial cells and demonstrated that suppression of CBP function results in loss of growth regulation and polarity. We also provide evidence that CBP functions in a positive feed-back loop with retinoids and the retinoic acid receptor-beta 2. In the final year of this grant we have shown that CBP regulates polarity and growth through modulation of laminin-5 expression. These findings provide important insight into how retinoid and retinoic acid receptors may act to regulate normal mammary epithelial cell growth and polarity. These findings also can be rapidly translatated to provide 1) biomarkers for breast cancer risk and 2) response to chemoprevention.